POS0330 SYNOVIAL M1 MACROPHAGES AND FIBROBLASTS DUAL-TARGETING LIPOSOMES ASSISTED DELIVERY OF TRIAMCINOLONE ACETONIDE IS EFFECTIVE AGAINST JOINT PAIN AND CARTILAGE DEGENERATION IN OSTEOARTHRITIS
Authors: C. Deng, Y. Chen, X. Zhao, L. Yu, Y. Xiao, H. LI, Y. Zhang, K. Ai, D. Zhou, X. Bai, T. Gong, J. Wei, C. Zeng, G. Lei
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> The latest professional guidelines recommend intra-articular (IA) glucocorticoids (GCs) for pain relief in patients with knee osteoarthritis (OA). However, their effect is small-to-moderate and short-term only<sup>[1]</sup>. There is also concern about the possible risk of cartilage deterioration caused by repeated IA GCs. M1 macrophages and activated synovial fibroblasts (SFs) mutually contribute to the propagation of joint pain and cartilage destruction in OA by constructing a positive feedback loop. To alleviate joint pain more effectively over a longer period without increasing the risk of cartilage deterioration, we developed nano-porous cellular membrane (NM) camouflaged liposome (NM@Lip) for targeted delivery of triamcinolone acetate (TA), one of the IA GCs most commonly used for OA, to both M1 macrophages and activated SFs in the synovium of osteoarthritic joints. <h3>Objectives</h3> To investigate the phenotypic reprogramming effect of TA-loaded NM@Lip (TA-NM@Lip) in M1 macrophages and activated SFs and determine their ability in relieving pain and alleviate OA progression in rodent models. <h3>Methods</h3> TA-NM@Lip was fabricated using the thin-film hydration method. The mRNA and protein levels of pathogenic mediators secreted by M1 macrophages and activated SFs treated with free TA, TA-loaded liposome (TA-Lip) or TA-NM@Lip for 24 h were measured using real-time PCR, RNA sequencing, ELISA and Immunofluorescence staining. To evaluate the joint retention time of NM@Lip, 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indodicarbocyanine, 4-chlorobenzenesulfonate salt (DiD) solution, DiD-loaded Lip or DiD-loaded NM@Lip was injected intra-articularly into the osteoarthritic joints of monosodium iodoacetate (MIA) rats and the fluorescence images were captured by In Vivo Imaging System for 28 days. To study the therapeutic effect of different TA formulations, triamcinolone acetonide injection (TA IR), TA-Lip, TA-NM@Lip, or blank NM@Lip was injected intra-articularly into the osteoarthritic knee of MIA rats at one week after MIA injection or at one week and five weeks after anterior cruciate ligament transection combined with partial medial meniscectomy (ACLT + pMMx) surgery. Mechanical allodynia and hind paw weight distribution were assessed to determine the rats' pain-related behavior. The phenotypic alteration ability and therapeutic efficacy of TA IR, TA-Lip, TA-NM@Lip, and NM@Lip were verified by micro-computed tomography, histological and immunofluorescence staining. <h3>Results</h3> TA-NM@Lip was the most efficient in downregulating the expression of M1-related genes and upregulating M2-related genes compared with other treatment groups. The mRNA and protein levels of pro-inflammatory cytokines, adhesion molecule and proteolytic enzyme secreted by activated SFs were significantly downregulated by TA-NM@Lip. NM@Lip was retained in the joint for up to 28 days and selectively distributed into both M1 macrophages and activated SFs in synovium with low distribution in cartilage. In MIA-induced model, a single IA injection of TA-NM@Lip attenuated synovitis and achieved complete pain relief without inducing adverse effects. In ACLT + pMMx-induced model, repeated TA-NM@Lip did not cause apoptosis of chondrocytes or damage cartilage and attenuated cartilage degeneration. <h3>Conclusion</h3> TA-NM@Lip exhibited extended joint-retention time and selectively remodeled the phenotype of synovial M1 macrophages and activated SFs in OA joints. This dual-targeting scaffold effectively attenuated synovitis, decreased cartilage degeneration, and achieved complete relief of joint pain in two distinct rodent models of OA. <h3>Reference</h3> [1]Juni P, Hari R, Rutjes AW, et al. Intra-articular corticosteroid for knee osteoarthritis. Cochrane Database Syst Rev 2015; 2015: CD005328 <h3>Acknowledgements</h3> This work was financially supported by the National Natural Science Foundation of China (82102630, 81930071, 82072502), the National Natural Science Foundation Regional Innovation and Development Joint Fund (U21A20352), the National Key Research and Development Project (2022YFC3601900, 2022YFC3601901, 2022YFC3601902, 2022YFC3601903, 2022YFC3601904, 2022YFC3601905, and 2022YFC2505500), the Natural Science Foundation of Hunan Province (2022JJ20100). <h3>Disclosure of Interests</h3> None Declared.